Nicotinic acid has been used to treat metabolic syndrome and dyslipidemia. However, nicotinic acid has undesirable side effects such as flushing and diarrhea. It is therefore desirable to provide improved nicotinic acid receptor agonists with improved efficacy at treating metabolic syndrome and dyslipidemia, yet without the undesirable side effects. The compounds of the present invention provide such improved nicotinic acid receptor agonists.
M. Ridi, Gazzetta Chim. Ital. (1950) vol. 80, p. 121 and M. Ridi, Gazzetta Chim. Ital. (1952) vol. 82, p. 23 disclose syntheses of barbituric acid derivatives. FR 2563223 discloses nucleoside analogs. T. Paterson et al., J. Chem. Soc., Perkins Trans. 1 (1972), vol. 8, pp. 1041-1050 discloses the synthesis of 8-substituted pyrido[2,3-d]pyrimidines. S. Rao, Indian J. Chem. (1974), 12(10), pp. 1028-1030 discloses the synthesis of pyrano[2,3-d]pyrimidines. M. Skof, Heterocycles, (1999), 51(5), pp. 1051-1058 discloses one step transformations of (S)-1-benzoyl-3-[(E)-dimethylaminomethylidene]-5-methoxycarbonyl-pyrrolidin-2-one into quinolizinyl- and 2H-2-pyranonyl-substituted alanine derivatives. R. Toplak J. Heterocyclic Chem. (1999), 36(1), pp. 225-235 discloses the synthesis of pyran-2-ones. However, the compounds of the above references differ from those of the present invention. WO 2004/110368 describes combination therapies for the treatment of hypertension comprising the combination of an anti-obesity agent and an anti-hypertensive agent. However, WO 2004/110368 fails to describe nicotinic acid receptor agonists, or combinations of one or more nicotinic acid receptor agonists with a second therapeutic agent.
WO 2005/000217 describes combination therapies for the treatment of dyslipidemia comprising the administration of a combination of an anti-obesity agent and an anti-dyslipidemic agent. However, WO 2005/000217 fails to describe nicotinic acid receptor agonists, or combinations of one or more nicotinic acid receptor agonists with a second therapeutic agent.
WO 2004/110375 describes combination therapies for the treatment of diabetes comprising the administration of a combination of an anti-obesity agent and an anti-diabetic agent. However, WO 2004/110375 fails to describe nicotinic acid receptor agonists, or combinations of one or more nicotinic acid receptor agonists with a second therapeutic agent.
US 2004/0122033 describes combination therapies for the treatment of obesity comprising the administration of a combination of an appetite suppressant and/or metabolic rate enhancers and/or nutrient absorption inhibitors. However, US 2004/0122033 fails to describe nicotinic acid receptor agonists, or combinations of one or more nicotinic acid receptor agonists with a second therapeutic agent. US 2004/0229844 describes combination therapies for treating atherosclerosis comprising the administration of a combination of nicotinic acid or another nicotinic acid receptor agonist and a DP receptor antagonist. However, the nicotinic acid agonists of US 2004/0229844 are quite different from those of the present invention.
WO2005/077950 describes xanthine derivatives which are agonists of the nicotinic acid receptor HM74A. However, the xanthine derivatives of WO2005/077950 are quite different from the compounds of the present invention.